This invention relates to compounds that inhibit the secretion of apolipoprotein B, and to methods of treating and/or preventing atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X. This invention also relates to methods of reducing the secretion of apolipoprotein B and/or inhibiting microsomal triglyceride transfer protein.
Microsomal triglyceride transfer protein (MTP) catalyzes the transport of triglycerides, cholesteryl esters and phospholipids, and MTP is involved in the assembly of lipoproteins that contain apolipoprotein B (apo B). Examples of lipoproteins that contain apo B include lipoprotein (a) [Lp(a)], low density lipoprotein (LDL), and very low density lipoprotein (VLDL), which is a precursor to LDL. Compounds that contain apo B are known to contribute to the formation of atherosclerotic lesions.
A noteworthy disease in which MTP plays a direct role is abetalipoproteinemia. This disease is characterized by the virtual absence of plasma lipoproteins containing apo B. For example, plasma triglyceride levels may be as low as a few mg/dl, and plasma cholesterol levels are often only 20-45 mg/dl. Interestingly, autopsies of patients having abetalipoproteinemia reveal that these patients are free of atherosclerosis. Recently, it has been discovered that this disease is caused by a defect in the MTP gene.
Compounds that inhibit MTP and/or apo B secretion are useful in the treatment and/or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, and Syndrome X. The inhibition of MTP and/or inhibition of apo B secretion typically results in the lowering of plasma concentrations of compounds that contain apo B.
In the treatment of obesity, one of the primary therapeutic goals is the suppression of caloric intake through appetite control. In order to effect practical appetite control, many therapeutic regimens have evolved such as the use of methodologies targeting certain central and peripheral biopsychological systems, including the use of periphery drugs that blunt either positive afferent information or intensify inhibitory afferent information. As such, these drugs may stimulate chemoreceptor activity in the gut or modulate gastrointestinal functioning via a network of neurotransmitters located in the enteric plexus. Other drugs may serve to mimic or perform surrogative functions for appetite-regulating factors in the blood, alter oxidative hepatic metabolism, adjust metabolic satiety signals or modify amino acid profiles. Finally, drugs may affect steroid levels reflecting energy metabolism, which, in turn, influences neuronal function, for example the corticosteroidal upregulation of adrenoreceptors in the paraventricular nucleus.
Generally, drugs affecting digestion or lipid absorption can be expected to alter the timing and pattern of nutritional information reaching the brain. Within the brain, drugs are believed to alter appetite via a number of neurotransmitter and neuromodulator systems at a variety of specific sites; however, the influence of central neurochemical activity on the expression of appetite is complex and involves numerous interactions between disparate loci and receptors resulting in shifts in the magnitude, direction and quality of feeding behavior.
While many cogent theories have been advanced based on data and direct observation, the physiology of the control of food intake is not well understood and interest in the development of safe and efficacious appetite controlling drugs remains high. See, for example, Kissilev et al., Ann. Rev. Nutr., 2:371-418 (1981) and Russek, et al., Appetite, 2:137-143 (1981).
Conventional therapeutic approaches to the treatment of obesity have traditionally focused on the regulation of energy intake. Unfortunately, there is now a growing awareness that, while moderation of caloric intake is initially effective in reducing body weight, such regimens are not particularly effective over the long-term. In response, alternative strategies requiring less rigorous observation of caloric consumption have been developed, including the use of agents that alter the absorption of dietary fat from the gastrointestinal tract.
The gastrointestinal digestion and absorption of ingested lipids consists of several steps. Following dispersion of bulk fat into finely emulsified droplets in the stomach, fatty acid esters are hydrolyzed enzymatically, partially by the action of gastric lipase in the stomach, but predominantly by pancreatic lipase in the upper small intestine. In recent years, studies concerning certain inhibitors of pancreatic lipase, orlistat for example, have indicated that treatment with such inhibitors may hold promise in the treatment of obesity. However, in view of the complexity of the genetic component of obesity and the psychologic factors involved in maintaining lifestyle habits, the long-term efficacy of such drugs in managing body weight and decreasing obesity-related medical complications is unknown. Thus, the identification of alternative therapeutic regimens remains desirable.
The treatment of obesity is also an important therapeutic goal for the reduction of secondary disorders, including diabetes, peripheral vascular disease, hypertension, and the like. Dietary lipids represent a significant source of calories and therapeutic approaches that reduce the absorption of lipids may include, for example, reduction in the intake, digestion or absorption of lipids. In order for dietary lipids to be absorbed, they must initially be converted by hydrolysis into monoacylglycerides and free fatty acids. The inhibition of this hydrolytic cleavage of triglycerides by lipase inhibitors results in decreased absorption of monoacylglycerides and free fatty acids leading to the decreased consumption of fat with concomitant reduction or prevention of the abnormalities related thereto.
In one aspect, the present invention provides a method of treating or preventing obesity in a patient in need thereof using a compound of the present invention, or a combination of a compound of the present invention with one or more additional anti-obesity agents.
The present invention also provides a method of reducing intestinal fat absorption in a patient in need thereof using a compound of the present invention, or a combination of a compound of the present invention with one or more additional anti-obesity agents.
The present invention also provides a method for reducing food intake in a patient in need thereof using a compound of the present invention, or a combination of a compound of the present invention with one or more additional anti-obesity agents.
The glycoprotein apolipoprotein (a), [apo(a)], is synthesized and secreted by hepatic cells, and in humans, circulates largely in association with LDL in the form of a hybrid lipoprotein referred to as Lp(a). The association between apo(a) and the major protein moiety of LDL, namely apolipoprotein B100 (apo B100), is mediated through covalent linkage of a single unpaired cysteine residue in apo(a) to a complimentary unpaired cysteine residue in the extreme carboxyl terminus of apo B100.
Interest in the biology of this lipoprotein species is driven by the observation that an elevated plasma level of Lp(a) in humans is associated with an increased risk for atherosclerotic heart and vascular disease. The lowering of Lp(a) levels, however., has proven problematic since various conventional methods that are effective in reducing levels of LDL are not as efficacious or consistent in lowering levels of Lp(a). For example, it has been reported that neomycin, alone or in combination with niacin., is effective in reducing Lp(a) levels when administered over a period of several weeks to years. See Spinler, et al., J. Ann. Pharmacother., 28: 343 (1994).
Alternatively, oral doses of fosinopril, an angiotensin-converting enzyme inhibitor, have been demonstrated to lower Lp(a) levels after 12 weeks of treatment; however, Lp(a) reduction was significant only in patients that showed improvement in renal function, and therefore, the Lp(a) lowering ability of fosinopril may simply be attributable to the indirect consequence of improved kidney function. See Keilani, et al., Ann. Inter. Med., 118:246 (1993).
Additionally, certain steroidal hormones, estrogen for example, are known to down-regulate Lp(a) levels. See, for example, Frazer, et al., Nature Genet., 9: 424 (1995). However, estrogen therapy alone is associated with an increased risk of endometrial carcinoma, and for this reason, estrogen is normally administered in combination with progesterone. Although short-term treatment with this estrogen/progesterone combination is an effective therapeutic strategy for reducing Lp(a) levels, long-term treatment, i.e. six months or more, does not result in the same degree of decreased inhibition as that observed for treatment with estrogen alone. See Soma, et al., Arch. Internal. Med., 153:1462 (1993), and Soma, et al., Chem. Phys. Lipids, 345, 67 (1994).
Furthermore, LDL apheresis has been shown to be an effective means for lowering Lp(a) levels. See Koizumi, et al., Atherosclerosis, 100: 65 (1993). However, apheresis is an invasive approach requiring weekly treatments and, therefore, is not regarded as a treatment of choice. Accordingly, improved methods of reducing plasma Lp(a) levels, or formation of Lp(a) precursors will have utility in the treatment of conditions and diseases arising from hyperbetalipoproteinemia, including, for example, atherosclerosis, myocardial infarction, stroke, restenosis following coronary bypass surgery or angioplasty procedures, and so forth.
While the precise mechanisms governing blood levels of Lp(a) are presently unknown, there is evidence to suggest that Lp(a) levels are regulated at the level of synthesis rather than catabolism. Accordingly, because it is known that inhibition of hepatic secretion of VLDL and apo B results in the pre-secretory degradation of apo B and concomitant decrease in hepatic apo B levels and because each Lp(a) particle contains one copy of apo(a) bound to apo B, it is believed that decreasing the concentration of hepatic apo B, by the administration of an apo B secretion/MTP inhibitor, will result in a lowering of Lp(a) secreted, and thereby, a lowering of blood Lp(a) levels.
The treatment of diabetes and the related disease states historically involved a reduction in the amounts of ingested digestible carbohydrates by modification of dietary habits, control of nutrient entry or pharmacologically with inhibitors of carbohydrate digestive enzymes. In order for complex carbohydrates to be absorbed, they must first be metabolized into their respective monosaccharides through the action of glucosidases. The inhibition of this metabolism of complex carbohydrates by glucosidases results in decreased or delayed digestion of carbohydrates resulting in decreased absorption of glucose and in the delay or prevention of the development of diabetic complications including, for example, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and the like.
The abnormality known as xe2x80x9cSyndrome Xxe2x80x9d is a metabolic disease characterized by insulin resistance with possible secondary abnormalities of obesity, hypertension, increased circulatory levels of triglyceride-containing VLDL""s, and a reduction in HDL. cholesterol. Accordingly, the condition has been shown to be associated with an increased risk for, inter alia, hyperlipidemia, atherosclerosis and coronary artery disease. See, for example, D. N. Brindley, et al., Progress in Obesity Research, 7:505-510 (1996).
Some apolipoprotein B secretion inhibitors and/or MTP inhibitors are disclosed in commonly assigned U.S. Pat. No. 5,919,795 and PCT Publication WO 98/23593.
The present invention provides compounds of Formula I 
stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs,
wherein
each Ra and Rb is independently hydrogen or C1-C8alkyl;
each n is independently 0, 1, 2 or 3;
each X is independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substitited heterocycloalkyl;
R1 is hydrogen or C1-C8alkyl; and
R2 is hydrogen, xe2x80x94(CRaRa)nxe2x80x94X, C1-C8alkyl, C1-C8substituted alkyl, 
or R1 and R2 together with the nitrogen atom to which they are bonded form a 3 to 7 membered heterocycloalkyl ring comprising from 1 to 3 heteroatoms.
In a preferred embodiment of the compounds of Formula I, Rb is hydrogen.
In another preferred embodiment of the compounds of Formula I, Rb is hydrogen and R1 is hydrogen.
In another preferred embodiment of the compounds of Formula I,
Rb is hydrogen;
R1 is hydrogen;
R2 is 
xe2x80x83or xe2x80x94C(RaRa)nxe2x80x94X; and
each X is independently aryl or heteroaryl.
In a preferred embodiment of the compounds of Formula I, when X is aryl or heteroaryl, the aryl group is phenyl and the heteroaryl group is pyridyl.
In another preferred embodiment of the compounds of Formula I,
R2 is xe2x80x94C(RaRa)nxe2x80x94X
each Ra is independently methyl, ethyl or hydrogen; and
X is phenyl or pyridyl.
In another preferred embodiment of the compounds of Formula I,
Rb is hydrogen;
R1 is hydrogen;
R2 is 
and each X is independently phenyl or pyridyl.
Also provided are compounds of Formula I 
stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs,
wherein
Rb is hydrogen;
R1 is hydrogen;
R2 is hydrogen, C1-C8alkyl, xe2x80x94(CH2)nxe2x80x94Q, 
xe2x80x83each Q is independently phenyl, pyridyl, substituted phenyl, substituted pyridyl, cycloalkyl, or heterocycloalkyl; and
n is 0, 1, 2, or 3.
In a preferred embodiment of the compounds of Formula I, when Q is substituted phenyl or substituted pyridyl, the substituents are selected from xe2x80x94OC1-C8alkyl, C1-C8alkyl or halogen.
The present invention provides the compound: 
The present invention provides the compound: 
The present invention provides the compound: 
The present invention provides the compound: 
The present invention provides the compound: 
The present invention provides the compound: 
Also provided are methods of treating or preventing atherosclerosis, the methods comprising the step of administering to a patient having or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing obesity, the methods comprising the step of administering to an obese patient or a patient at risk of becoming obese a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing hypercholesterolemia, the methods comprising the step of administering to a patient having or at risk of having hypercholesterolemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing hyperlipidemia, the methods comprising the step of administering to a patient having or at risk of having hyperlipidemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing hypertriglyceridemia, the methods comprising the step of administering to a patient having or at risk of having hypertriglyceridemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrug.
Also provided are methods of treating or preventing hypoalphalipoproteinemia, the methods comprising the step of administering to a patient having or at risk of having hypoalphalipoproteinemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing pancreatitis, the methods comprising the step of administering to a patient having or at risk of having pancreatitis a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing diabetes, the methods comprising the step of administering to a patient having or at risk of having diabetes a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
In a preferred embodiment of the method of treating diabetes, the diabetes is non-insulin dependent diabetes mellitus (Type II).
Also provided are methods of treating or preventing myocardial infarction, the methods comprising the step of administering to a patient having or at risk of having myocardial infarction a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods method of treating or preventing a stoke, the methods comprising the step of administering to a patient having or at risk of having a stroke a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing restenosis, the methods comprising the step of administering to a patient having or at risk of having restenosis a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing Syndrome X, the methods comprising the step of administering to a patient having or at risk of having Syndrome X a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of inhibiting apolipoprotein B secretion, the methods comprising administering to a patient in need of apolipoprotein B secretion inhibition an apolipoprotein B secretion inhibiting amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of inhibiting microsomal triglyceride transfer protein, the methods comprising administering to a patient in need of microsomal triglyceride transfer protein inhibition a microsomal triglyceride transfer protein inhibiting amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are pharmaceutical composition comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
The present invention provides the compounds:
7-amino-quinoline-3-carboxylic acid ethyl ester;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (dipyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (dipyridin-2-yl-methyl)-amide, ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (dipyridin-2-yl-methyl)-amide, bis-ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide, ethanesulfonate;
(S)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
(S)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide, ethanesulfonate;
(S)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide, bis-ethanesulfonate;
(R)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
(R)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide, ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide, bis-ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-carbamoyl-2-phenyl-ethyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (carbamoyl-phenyl-methyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid propylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (2,2,2-trifluoro-ethyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid cyclopentylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-phenyl-propyl)-amide;
(R)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-phenyl-ethyl)-amide, ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-phenyl-ethyl)-amide, ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
(R)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
(R)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3carboxylic acid (1-pyridin-2-yl-propyl)-amide, ethanesulfonate;
(S)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
(S)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide, ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (pyridin-2-ylmethyl)-amide, ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (2-pyridin-2-yl-ethyl)-amide, ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethylamide, ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid butylamide, ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (thiophen-2-ylmethyl)-amide, ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;
(S)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
(R)-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide ethanesulfonate;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 4-methoxy-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 4-chloro-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 4-methyl-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid cyclopropylmethyl-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 4-fluoro-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid isopropyl-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid benzhydryl-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid cyclopropylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid [1-(4-fluoro-phenyl)-ethyl]-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 3-methyl-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 3-methoxy-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 3-chloro-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 2-fluoro-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 3-fluoro-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 2-methyl-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 2-methoxy-benzylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid 2-chloro-benzylamide;
4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [3-(pyrrolidine-1-carbonyl)-quinolin-7-yl]-amide;
4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [3-(morpholine-4-carbonyl)-quinolin-7-yl]-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid diethylamide; and
4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [3-(piperidine-1-carbonyl)-quinolin-7-yl]-amide, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are kits for the treatment or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, and Syndrome X, the kits comprising:
a) a first pharmaceutical composition comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
b) a second pharmaceutical composition comprising a second compound useful for the treatment or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X; and
c) a container for containing the first and second compositions.
Also provided are methods for the treatment or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X, the methods comprising the step of administering to a patient having or at risk of having atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs in combination with at least one additional compound useful for the treatment or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X.
In a preferred embodiment of the method, the additional compound is a HMG-CoA reductase inhibitor.
In another preferred embodiment of the method, the additional compound is a MTP inhibitor.
In another preferred embodiment of the method, the additional compound is a HMG-CoA synthase inhibitor.
In another preferred embodiment of the method, the additional compound is an ACAT inhibitor.
In another preferred embodiment of the method, the additional compound is a CETP inhibitor.
In another preferred embodiment of the method, the additional compound is a lipase inhibitor.
In another preferred embodiment of the method, the additional compound is a glucosidase inhibitor.
Also provided are pharmaceutical compositions comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrug, and at least one additional compound useful for the treatment or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X.
In a preferred composition, the additional compound is a HMG-CoA reductase inhibitor.
In another preferred composition, the additional compound is a MTP inhibitor.
In a preferred composition the additional compound is a HMG-CoA synthase inhibitor.
In another preferred composition, the additional compound is an ACAT inhibitor.
In another preferred composition, the additional compound is a CETP inhibitor.
In another preferred composition, the additional compound is a lipase inhibitor.
In another preferred composition, the additional compound is a glucosidase inhibitor.
The present invention also provides compounds of Formula II 
stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs,
wherein
each R3 is independently hydrogen or C1-C6alkyl;
each RQ is independently hydrogen or C1-C6alkyl;
A is 
X is O or S;
n is 0 to 6;
each Rb is independently hydrogen, xe2x80x94CF3, xe2x80x94OC1-C6alkyl, halo, xe2x80x94SH, xe2x80x94SC1-C6alkyl, phenyl, or xe2x80x94C1-C6alkyl;
B is hydrogen, 
xe2x80x83or B and RQ together with the nitrogen atom to which they are bonded form a heterocycloalkyl ring comprising from 1 to 3 heteroatoms;
each R is independently hydrogen or C1-C6alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl,
wherein any substituents are independently selected from xe2x80x94CF3, halo, xe2x80x94OC1-C6alkyl, or xe2x80x94C1-C6alkyl; and
m is 0 to 5.
In a preferred embodiment of the compounds of Formula II, A is 
In another preferred embodiment of the compounds of Formula II, each RQ is hydrogen.
In another preferred embodiment of the compounds of Formula II, R3 is hydrogen.
In another preferred embodiment of the compounds of Formula II, B is 
and each Y is independently phenyl or pyridyl.
Also provided by the present invention are the compounds:
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid [bis-(4-fluoro-phenyl)-methyl]-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid benzyl-ethyl-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (3-phenyl-propyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl-pyridin-2-ylmethyl-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid phenethyl-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid phenylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (2-methoxy-ethyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-methyl-3-phenyl-propyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid indan-1-ylamide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (3,3-diphenyl-propyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid [2-(1H-indol-3-yl)-ethyl]-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (4-phenyl-butyl)-amide;
[R]-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid [(4-fluoro-phenyl)-pyridin-2-yl-methyl]-amide;
[S]-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid [(4-fluoro-phenyl)-pyridin-2-yl-methyl]-amide;
2-methyl-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (2-methoxy-ethyl)-amide;
[S]-2-methyl-7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
[R]-7-[2-(5-trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
[R]-7-[2-(5-trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
[S]-7-[2-(5-trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
[R]-7-[2-(6-methyl-pyridin-3-yl)-benzoylamino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
[R]-7-[2-(5-methyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
[S]-7-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
[R]-7-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
[R]-7-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
[R]-7-[(2-p-tolyl-pyridine-3-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
[R]-7-{[2-(4-isopropyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
[R]-7-{[2-(4-tert-butyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
[R]-7-{[2-(4-methoxy-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
[R]-7-{[2-(4-ethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
7-[(4xe2x80x2-tert-butyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-[(biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-methyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-methyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid acid (di-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-methyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid acid (1-pyridin-2-yl-propyl)-amide;
7-(2-benzofuran-2-yl-benzoylamino)-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-isopropyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-isopropyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-isopropyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-[(3xe2x80x2-methyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-ethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-ethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-[(4xe2x80x2-tert-butyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-[(4xe2x80x2-ethylsulfanyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-ethylsulfanyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-(2-naphthalen-2-yl-benzoylamino)-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-(2-benzo[1,3]dioxol-5-yl-benzoylamino)-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(3xe2x80x2,4xe2x80x2-dimethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(2xe2x80x2-methyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(3xe2x80x2-fluoro-4xe2x80x2-methyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-ethoxy-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-ethoxy-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-[(4xe2x80x2-ethoxy-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-[2-(2,3-dihydro-benzofuran-5-yl)-benzoylamino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-propoxy-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-propoxy-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-[(4xe2x80x2-butoxy-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(4xe2x80x2-butoxy-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-[(3-methyl-4-oxo-2-phenyl-4H-chromene-8-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-[(3-methyl-4-oxo-2-phenyl-4H-chromene-8-carbonyl)-amino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[(3-methyl-4-oxo-2-phenyl-4H-chromene-8-carbonyl)-amino]-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-(2-cyclohexylmethoxy-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-(2-cyclohexylmethoxy-benzoylamino)-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-(2-cyclohexylmethoxy-benzoylamino)-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-(2-cyclohexylmethoxy-3-methoxy-benzoylamino)-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-(2-cyclohexylmethoxy-3-methoxy-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-(2-cyclohexylmethoxy-3-methoxy-benzoylamino)-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-[2-(bicyclo[2.2.1]hept-2-ylmethoxy)-benzoylamino]-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-[2-(bicyclo[2.2.1]hept-2-ylmethoxy)-benzoylamino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-[2-(bicyclo[2.2.1]hept-2-ylmethoxy)-benzoylamino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-[2-(bicyclo[2.2.1]hept-2-ylmethoxy)-3-methoxy-benzoylamino]-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-[2-(bicyclo[2.2.1]hept-2-ylmethoxy)-3-methoxy-benzoylamino]-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
-[2-(bicyclo[2.2.1]hept-2-ylmethoxy)-3-methoxy-benzoylamino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
-(2-pentyloxy -benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-(2-pentyloxy -benzoylamino)-quinoline-3-carboxylic (phenyl-pyridin-2-yl-methyl)-amide;
7-(2-pentyloxy -benzoylamino)-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-(3-methoxy-2-pentyloxy-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-(3-methoxy-2-pentyloxy-benzoylamino)-quinoline-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide;
7-(3-methoxy-2-pentyloxy-benzoylamino)-quinoline-3-carboxylic acid (1-pyridin-2-yl-propyl)-amide;
7-(2-benzyloxy-3-methoxy-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-(2-cyclopentylethoxy-3-methoxy-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-[3-methoxy-2-(4,4,4-trifluoro-butoxy)-benzoylamino]-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
-7-[3-methoxy-2-(3-methyl-butoxy)-benzoylamino]-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-(2-cyclobutylmethoxy-3-methoxy-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-(2-cyclopentylmethoxy-3-methoxy-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
2-hexyloxy-3-methoxy-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-(2-cyclohexylethoxy-3-methyl-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
7-(2-cyclohexylmethoxy-3-methyl-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide;
2-methyl-7-[2-(5-trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
2-methyl-7-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
2-ethyl-7-[2-(5-trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
2-ethyl-7-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
7-{[6-methyl-2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
7-[(6-methyl-4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
7-[3-methyl-2-(5-trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide;
7-[3,5-dimethyl-2-(5-trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (1-pyridin-2-yl-ethyl)-amide; or
7-(3-chloro-2-cyclohexylmethoxy-benzoylamino)-quinoline-3-carboxylic acid (di-pyridin-2-yl-methyl)-amide, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing atherosclerosis, the methods comprising the step of administering to a patient having or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of treating or preventing obesity, the methods comprising the step of administering to an obese patient or a patient at risk of becoming obese a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of treating or preventing hypercholesterolemia, the methods comprising the step of administering to a patient having or at risk of having hypercholesterolemia a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of treating or preventing hyperlipidemia, the methods comprising the step of administering to a patient having or at risk of having hyperlipidemia a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of treating or preventing hypertriglyceridemia, the methods comprising the step of administering to a patient having or at risk of having hypertriglyceridemia a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of treating or preventing hypoalphalipoproteinemia, the methods comprising the step of administering to a patient having or at risk of having hypoalphalipoproteinemia a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of treating or preventing pancreatitis, the methods comprising the step of administering to a patient having or at risk of having pancreatitis a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of treating or preventing diabetes, the methods comprising the step of administering to a patient having or at risk of having diabetes a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
In a preferred embodiment of the method of treating diabetes, the diabetes is non-insulin dependent diabetes mellitus (Type II).
Also provided are methods of treating or preventing myocardial infarction, the methods comprising the step of administering to a patient having or at risk of having myocardial infarction a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of treating or preventing a stoke, the methods comprising the step of administering to a patient having or at risk of having a stroke a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of treating or preventing restenosis, the methods comprising the step of administering to a patient having or at risk of having restenosis a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of treating or preventing Syndrome X, the methods comprising the step of administering to a patient having or at risk of having Syndrome X a therapeutically effective amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of inhibiting apolipoprotein B secretion, the methods comprising administering to a patient in need of apolipoprotein B secretion inhibition an apolipoprotein B secretion inhibiting amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are methods of inhibiting microsomal triglyceride transfer protein, the methods comprising administering to a patient in need of microsomal triglyceride transfer protein inhibition a microsomal triglyceride transfer protein inhibiting amount of a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are pharmaceutical compositions comprising a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
Also provided are kits for the treatment or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X, the kits comprising:
a) a first pharmaceutical composition comprising a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.
b) a second pharmaceutical composition comprising a second compound useful for the treatment or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X; and
c) a container for containing the first and second compositions.
Also provided are methods for the treatment or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X, the methods comprising the step of administering to a patient having or at risk of having atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X a therapeutically effective amount of a compound of Formula II, a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug in combination with at least one additional compound useful for the treatment or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X.
Also provided are pharmaceutical compositions comprising a compound of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, and at least one additional compound useful for the treatment or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X.
Also provided are the compounds:
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (pentylcarbamoyl-phenyl-methyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (diethylcarbamoyl-phenyl-methyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid -S-(pentylcarbamoyl-phenyl-methyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid -S-(diethylcarbamoyl-phenyl-methyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid -R-(pentylcarbamoyl-phenyl-methyl)-amide;
7-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid -R-(diethylcarbamoyl-phenyl-methyl)-amide, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
The present invention relates to compounds of Formula I and II, pharmaceutically acceptable salts of compounds of Formula I and II, prodrugs of compounds of Formula I and II, and pharmaceutically acceptable salts of the prodrugs of compounds of Formula I and II. The present invention also relates to methods of treatment and/or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, and Syndrome X. In addition, the present invention relates to methods of inhibiting MTP and/or inhibiting the secretion of apolipoprotien B. Certain terms that are used in this application are defined below.
The term xe2x80x9calkylxe2x80x9d means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, and hexyl.
The term xe2x80x9calkoxyxe2x80x9d means an alkyl group bonded to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy. Preferred alkoxy groups are C1-C8alkoxy.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
The term xe2x80x9calkenylxe2x80x9d means a branched or straight chain hydrocarbon having one or more carbon-carbon double bonds.
The term xe2x80x9calkynylxe2x80x9d means a branched or straight chain hydrocarbon having one or more carbon-carbon triple bonds.
The term xe2x80x9ccycloalkylxe2x80x9d means a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred cycloalkyl groups are C3-C8cyloalkyl. It is also possible for the cycloalkyl group to have one or more double bonds, but is not aromatic. Examples of cycloalkyl groups having a double bond include cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclobutadienyl, and the like.
The term xe2x80x9cperfluoroalkylxe2x80x9d means an alkyl group in which all of the hydrogen atoms have been replaced with fluorine atoms.
The term xe2x80x9cacylxe2x80x9d means a group derived from an organic acid (xe2x80x94COOH) by removal of the hydroxy group (xe2x80x94OH).
The term xe2x80x9carylxe2x80x9d means a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl.
The term xe2x80x9cheteroatomxe2x80x9d includes oxygen, nitrogen, sulfur, and phosphorous.
The term xe2x80x9cheteroarylxe2x80x9d means an aromatic ring containing one or more heteroatoms. If the heteroaryl group contains more than one heteroatoms, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl, indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, isothiazolyl, and benzo[b]thienyl. Preferred heteroaryl groups are five and six membered rings and contain from one to three heteroatoms.
The term xe2x80x9cheterocycloalkylxe2x80x9d mean a cycloalkyl group in which one or more of the carbon atoms has been replaced with a heteroatom. If the heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heterocycloalkyl groups include tetrahydrofuryl, morpholinyl, piperazinyl, piperidyl, and pyrrolidinyl. Preferred heterocycloalkyl groups are five and six membered rings and contain from one to three heteroatoms. It is also possible for the heterocycloalkyl group to have one or more double bonds, but is not aromatic. Example of heterocycloalkyl groups containing double bonds include dihydrofuran, and the like.
It is also noted that the cyclic ring groups, i.e., aryl, heteroaryl, cycloalkyl, heterocycloalkyl, can comprise more than one ring. For example, the naphthyl group is a fused bicyclic ring system. It is also intended that the present invention include ring groups that have bridging atoms, or ring groups that have a spiro orientation.
Representative examples of five to six membered aromatic rings, optionally having one or two heteroatoms, are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
Representative examples of partially saturated, fully saturated or fully unsaturated five to eight membered rings, optionally having one to three heteroatoms, are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further exemplary five membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazaolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazaolyl, 1,3,4-thiadiazolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl ,and 1,3-oxathiolyl.
Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, and 1 ,4,2-oxadiazinyl.
Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-triazepinyl.
Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.
Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.
A cyclic ring group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended. For example, the term xe2x80x9cpyridylxe2x80x9d includes 2-, 3-, or 4-pyridyl, and the term xe2x80x9cthienylxe2x80x9d includes 2-, or 3-thienyl.
The term xe2x80x9csubstitutedxe2x80x9d means that a hydrogen atom on a molecule has been replaced with a different atom or with a molecule. The atom or molecule replacing the hydrogen atom is called a substituent. Examples of suitable substituents include, halogen, xe2x80x94OC1-C8alkyl, xe2x80x94C1-C8alkyl, xe2x80x94CF3, xe2x80x94NH2, xe2x80x94NHC1-C8alkyl, xe2x80x94N(C1-C8alkyl)2, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2C1-C8alkyl, and the like.
The symbol xe2x80x9cxe2x80x94xe2x80x9d represents a covalent bond.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d means an amount of a compound that ameliorates, attenuates, or eliminates one or more symptoms of a particular disease or condition or prevents or delays the onset of one of more symptoms of a particular disease or condition.
The term xe2x80x9cpatientxe2x80x9d means animals, such as dogs, cats, cows, horses, sheep, geese, and humans. Particularly preferred patients are mammals, including both males and females.
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means that the substance or composition must be compatible with the other ingredients of a formulation, and not deleterious to the patient.
The phrases xe2x80x9ca compound of the present invention, a compound of Formula I (or II), or a compound in accordance with Formula I (or II)xe2x80x9d and the like include the pharmaceutically acceptable salts of the compounds, prodrugs of the compounds, and pharmaceutically acceptable salts of the prodrugs.
The terms xe2x80x9creaction-inert solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d refer to a solvent or mixture of solvents that does not interact with starting materials, reagents, intermediates or products in a manner that adversely affects the desired product.
The terms xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d include preventative (e.g., prophylactic) and palliative treatment.
The term xe2x80x9cMTP inhibitorxe2x80x9d refers to any substance or agent or any combination of substances and/or agents that reduces, retards, or eliminates the biological action of MTP.
The term xe2x80x9capo B secretion inhibitorxe2x80x9d refers to any substance or agent or any combination of substances and/or agents that reduces, retards, or eliminates the secretion of apo B resulting in lowered plasma levels of at least one compound containing apo B.
A patient in need of MTP inhibition and/or apo B secretion inhibition is a patient having a disease or condition in which MTP and/or apo B plays a role in the disease or condition. Examples of patients in need of MTP inhibition and/or apo B inhibition include patients having or at risk of having diabetes (including Type I and Type II, impaired glucose tolerance, insulin resistance, and diabetic complications, such as nephropathy, retinopathy, neuropathy and cataracts), atherosclerosis, obesity, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X.
The characteristics of patients at risk of having atherosclerosis are well known to those in the art and include patients who have a family history of cardiovascular disease, including hypertension and atherosclerosis, obese patients, patients who exercise infrequently, patients with hypercholesterolemia, hyperlipidemia and/or hypertriglyceridemia, patients having high levels of LDL or Lp(a), patients having low levels of HDL (hypoalphalipoproteinemia), and the like.
Patients at risk of developing diabetes include patients who have a family history of diabetes, obese patients, patients who exercise infrequently, patients who have polycystic ovary syndrome, impaired glucose tolerance or exhibit insulin resistance, and patients who have or have had gestational diabetes. The preferred type of diabetes to be treated by the compounds of the present invention is non-insulin dependent diabetes mellitus, also known as Type II diabetes or NIDDM. It is also noted that the complications associated with diabetes can be treated or prevented through the methods disclosed herein.
Patients who are at risk of developing restenosis include patients who have undergone angioplasty procedures, or who have had bypass surgery. In general restenosis can occur whenever a blood vessel has been damaged or stressed. Balloon angioplasty is the most common type of angioplasty.
Patients who are at risk of having myocardial infarction are patients who are obese, have cardiovascular diseases, such as atherosclerosis, high cholesterol, or hypertension, and the like. In addition, patients having diabetes are at risk of developing cardiovascular diseases to a higher extent than persons not having diabetes. Such development of cardiovascular diseases can result in myocardial infarction.
Patients who are at risk of having a stoke include patients having atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, diabetes, patients undergoing angioplasty procedures, bypass surgery or any other form of surgery, obese patients, and the like. Treating or preventing atherosclerosis, helps to lower the probability of having a stroke.
The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition. In addition, the compounds or compositions can be administered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.
In addition, the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds. The other pharmaceutically active compounds can be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously, or sequentially. For example, in the case of tablets, the active compounds may be found in one tablet or in separate tablets, which can be administered at once or sequentially. In addition, it should be recognized that the compositions may be different forms. For example, one or more compounds may be delivered via a tablet, while another is administered via injection or orally as a syrup. All combinations, delivery methods and administration sequences are contemplated.
Since one aspect of the present invention contemplates the treatment of the disease/conditions with a combination of pharmaceutically active agents that may be administered separately, the invention further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, a prodrug thereof, or a salt of such compound or prodrug; and a second pharmaceutically active compound. The kit comprises a container for containing the separate compositions, such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, bags, and the like. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows xe2x80x9cFirst Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . xe2x80x9d etc. Other variations of memory aids will be readily apparent. A xe2x80x9cdaily dosexe2x80x9d can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of compounds of the present invention can consist of one tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this and aid in correct administration of the active agents.
In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
The compounds of the present invention and other pharmaceutically active agents, if desired, can be administered to a patient either orally, rectally, parenterally, (for example, intravenously, intramuscularly, or subcutaneously) intracisternally, intravaginally, intraperitoneally, intravesically, locally (for example, powders, ointments or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, triglycerides, including vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. A preferred carrier is Miglyol(copyright). Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of microorganism contamination of the compositions can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, gycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, as for example, paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and/or (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be used as fillers in soft or hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, Miglyol(copyright), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administration are preferable suppositories, which can be prepared by mixing a compound of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalants. The active compound or compounds are admixed under sterile conditions with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required. Opthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
In a preferred method of administering a compound of the present invention, the administration occurs prior to or during a somnolent period. The phrase xe2x80x9csomnolent periodxe2x80x9d refers to a time frame when the patient is sleeping. The apo B secretion inhibitor and/or MTP inhibitor of the present invention is preferably administered prior to the normal sleeping period but can be administered during the somnolent period. An exemplary time for administering a compound of the present invention is at bedtime. It is noted that the somnolent period can be anytime during which the patient sleeps and includes day and night.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 3,000 mg per day. A preferred dosage for a human is about 1 mg to about 1,000 mg per day. A more preferred dose is from about 1 mg to about 100 mg per day. The specific dosage and dosage range that can be used depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular patient is well within the ordinary skill in the art.
The following paragraphs describe exemplary formulations, dosages etc. useful for non-human animals. The administration of a compound of the present invention can be effected orally or non-orally, for example by injection. An amount of a compound of the present invention is administered such that an effective dose is received, generally a daily dose which, when administered orally to an animal is usually between 0.01 and 1000 mg/kg of body weight, preferably between 0.1 and 50 mg/kg of body weight. Conveniently, the compound can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply. The compound can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water soluble salt). Conveniently, the compound can also be added directly to the feed, as such, or in the form of an animal feed supplement, also referred to as a premix or concentrate. A premix or concentrate of the compound in a carrier is more commonly employed for the inclusion of the agent in the feed. Suitable carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and mineral mixes such as are commonly employed in poultry feeds. A particularly effective carrier is the respective animal feed itself; that is, a small portion of such feed. The carrier facilitates uniform distribution of the compound in the finished feed with which the premix is blended. It is important that the compound be thoroughly blended into the premix and, subsequently, the feed. In this respect, the compound may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then blended with the carrier. It will be appreciated that the proportions of compound in the concentrate are capable of wide variation since the amount of active compound in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of compound.
High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements which are suitable for direct feeding to animals. In such instances, the animals are permitted to consume the usual diet. Alternatively, such concentrated supplements may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of a compound of the present invention. The mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity.
If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the compound material across the top of the dressed feed.
The preferred medicated swine, cattle, sheep and goat feed generally contain from 1 to 400 grams of a compound of the present invention per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed.
The preferred poultry and domestic pet feeds usually contain about 1 to 400 grams and preferably 10 to 400 grams of a compound of the present invention per ton of feed.
For parenteral administration in animals, the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal.
In general, parenteral administration involves injection of a sufficient amount of a compound of the present invention to provide the animal with 0.01 to 100 mg/kg/day of body weight of the active ingredient. The preferred dosage for poultry, swine, cattle, sheep, goats and domestic pets is in the range of from 0.1 to 50 mg/kg/day.
Paste formulations can be prepared by dispersing a compound of the present invention in pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
Pellets containing an effective amount of a compound of the present invention can be prepared by admixing a compound of the present invention with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process.
It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level. Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper active agent level in the animal""s body.
The terms pharmaceutically acceptable salts, esters, amides, or prodrugs means the carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use with patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
The term xe2x80x9csaltsxe2x80x9d refers to inorganic and organic salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, besylate, esylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J Pharm Sci, 66:1-19 (1977).
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of the present invention, if applicable, include C1-C8 alkyl esters. Acceptable esters also include C5-C7cycloalkyl esters, as well as arylalkyl esters such as benzyl. C1-C4 alkyl esters are preferred. Esters of compounds of the present invention may be prepared according to methods that are well known in the art.
Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include amides derived from ammonia, primary C1-C8alkyl amines, and secondary C1-C8 dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom. Amides derived from ammonia, C1-C3 primary alkyl amines, and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art.
The term xe2x80x9cprodrugxe2x80x9d means compounds that are transformed in vivo to yield a compound of the present invention. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A good discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound of the present invention contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C1-C8)alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as xcex2-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
Similarly, if a compound of the present invention comprises an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, xcex1-amino(C1-C4)alkanoyl, arylacyl and xcex1-aminoacyl, or xcex1-aminoacyl-xcex1-aminoacyl, where each xcex1-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, xe2x80x94P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
If a compound of the present invention comprises an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRRxe2x80x2-carbonyl where R and Rxe2x80x2 are each independently ((C1-C10)alkyl, (C3-C7)cyCloalkyl, benzyl, or R-carbonyl is a natural xcex1-aminoacyl or natural xcex1-aminoacyl-natural xcex1-aminoacyl, xe2x80x94C(OH)C(O)OY wherein (Y is H, (C1-C6)alkyl or benzyl), xe2x80x94C(OY0)Y1 wherein Y0 is (C1-C4) alkyl and Y1 is ((C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N- or dixe2x80x94N,Nxe2x80x94(C1-C6)alkylaminoalkyl, xe2x80x94C(Y2)Y3 wherein Y2 is H or methyl and Y3 is mono-N- or dixe2x80x94N,Nxe2x80x94(C1-C6)alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.
The compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if a compound contains a double bond, both the cis and trans forms, as well as mixtures, are contemplated.
Mixtures of isomers, including stereoisomers can be separated into their individual isomers on the basis of their physical chemical differences by methods well know to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of this invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The present invention contemplates and encompasses both the solvated and unsolvated forms.
It is also possible that compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. For example, all of the tautomeric forms of the imidazole moiety are included in this invention. Also, for example, all keto-enol or imine-enamine forms of the compounds are included in this invention.
Those skilled in the art will recognize that the compound names contained herein may be based on a particular tautomer of a compound. While the name for only a particular tautomer may be used, it is intended that all tautomers are encompassed by the name of the particular tautomer and all tautomers are considered part of the present invention.
It is also intended that the invention disclosed herein encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.
The present invention also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 33P, 32P, 35S, 18F, 125I, 131I, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
In one aspect, the present invention concerns the treatment of diabetes, including impaired glucose tolerance, insulin resistance, insulin dependent diabetes mellitus (Type I) and non-insulin dependent diabetes mellitus (NIDDM or Type II). Also included in the treatment of diabetes are the diabetic complications, such as neuropathy, nephropathy, retinopathy or cataracts.
Diabetes can be treated by administering to a patient having diabetes (Type I or Type II), insulin resistance, impaired glucose tolerance, or any of the diabetic complications such as neuropathy, nephropathy, retinopathy or cataracts, a therapeutically effective amount of a compound of the present invention. It is also contemplated that diabetes be treated by administering a compound of the present invention along with other agents that can be used to treat diabetes.
Representative agents that can be used to treat diabetes include insulin and insulin analogs (e.g. LysPro insulin); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH2; sulfonylureas and analogs: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide(copyright)), glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; xcex12-antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, A-4166; glitazones: ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, BRL49653; fatty acid oxidation inhibitors: clomoxir, etomoxir; xcex1-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; xcex2-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243; phosphodiesterase inhibitors: L-386,398; lipid-lowering agents: benfluorex; antiobesity agents: fenfluramine and orlistat; vanadate and vanadium complexes (e.g. Naglivan(copyright)) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents: nicotinic acid, acipimox, WAG 994; and glycogen phosphorylase inhibitors, such as those disclosed in WO 96/39385 and WO 96/39384. Also contemplated in combination with compounds of the present invention are pramlintide acetate (Symlin(trademark)) and nateglinide. Any combination of agents can be administered as described above.
In addition, the compounds of the present invention can be administered in combination with other pharmaceutical agents such as cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors, especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors, HMG-CoA reductase and synthase gene expression inhibitors, CETP inhibitors, biles acid sequesterants, fibrates, ACAT inhibitors, squalene synthetase inhibitors, anti-oxidants and niacin. The compounds of the present invention may also be administered in combination with naturally occurring compounds that act to lower plasma cholesterol levels. These naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract, Benecol(copyright), and niacin.
Specific cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors are described in detail below. Additional cholesterol absorption inhibitors are known to those skilled in the art and are described, for example, in PCT WO 94/00480.
Any HMG-CoA reductase inhibitor may be employed as an additional compound in the combination therapy aspect of the present invention. The term HMG-CoA reductase inhibitor refers to a compound that inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme A to mevalonic acid as catalyzed by the enzyme HMG-CoA reductase. Such inhibition may be determined readily by one of skill in the art according to standard assays (e.g., Methods of Enzymology, 71: 455-509 (1981); and the references cited therein). A variety of these compounds are described and referenced below. U.S. Pat. No. 4,231,938 discloses certain compounds isolated after cultivation of a microorganism belonging to the genus Aspergillus, such as lovastatin. Also, U.S. Pat. No. 4,444,784 discloses synthetic derivatives of the aforementioned compounds, such as simvastatin. Additionally, U.S. Pat. No. 4,739,073 discloses certain substituted indoles, such as fluvastatin. Further, U.S. Pat. No. 4,346,227 discloses ML-236B derivatives, such as pravastatin. In addition, EP 491,226 teaches certain pyridyldihydroxyheptenoic acids, such as rivastatin. Also, U.S. Pat. No. 4,647,576 discloses certain 6-[2-(substituted-pyrrol-1-yl)-alkyl]-pyran-2-ones such as atorvastatin. Other HMG-CoA reductase inhibitors will be known to those skilled in the art. Examples of marketed products containing HMG-CoA reductase inhibitors that can be used in combination with compounds of the present invention include Baycol(copyright), Lescol(copyright), Lipitor(copyright), Mevacor(copyright), Pravachol(copyright) and Zocor(copyright).
Any HMG-CoA synthase inhibitor may be used as the second compound in the combination therapy aspect of this invention. The term HMG-CoA synthase inhibitor refers to a compound which inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Such inhibition may be determined readily by one of skill in the art according to standard assays (e.g., Methods of Enzymology, 35:155-160 (1975); and Methods of Enzymology, 110: 19-26 (1985); and the references cited therein). A variety of these compounds are described and referenced below. U.S. Pat. No. 5,120,729 discloses certain beta-lactam derivatives. U.S. Pat. No. 5,064,856 discloses certain spiro-lactone derivatives prepared by culturing the microorganism MF5253. U.S. Pat. No. 4,847,271 discloses certain oxetane compounds such as 11-(3-hydroxymethyl4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undecadienoic acid derivatives. Other HMG-CoA synthase inhibitors will be known to those skilled in the art.
Any compound that decreases HMG-CoA reductase gene expression may be used as the second compound in the combination therapy aspect of this invention. These agents may be HMG-CoA reductase transcription inhibitors that block the transcription of DNA or translation inhibitors that prevent translation of mRNA coding for HMG-CoA reductase into protein. Such inhibitors may either affect transcription or translation directly, or may be biotransformed into compounds that have the aforementioned attributes by one or more enzymes in the cholesterol biosynthetic cascade or may lead to the accumulation of an isoprene metabolite that has the aforementioned activities. Such regulation is readily determined by those skilled in the art according to standard assays (Methods of Enzymology, 110: 9-19 1985). Several such compounds are described and referenced below however other inhibitors of HMG-CoA reductase gene expression will be known to those skilled in the art. U.S. Pat. No. 5,041,432 discloses certain 15-substituted lanosterol derivatives. Other oxygenated sterols that suppress the biosynthesis of HMG-CoA reductase are discussed by E. I. Mercer (Prog. Lip. Res., 32:357-416 1993).
Any compound having activity as a CETP inhibitor can serve as the second compound in the combination therapy aspect of the instant invention. The term CETP inhibitor refers to compounds that inhibit the cholesteryl ester transfer protein (CETP) mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL. A variety of these compounds are described and referenced below however other CETP inhibitors will be known to those skilled in the art. U.S. Pat. No. 5,512,548 discloses certain polypeptide derivatives having activity as CETP inhibitors, while certain CETP-inhibitory rosenonolactone derivatives and phosphate-containing analogs of cholesteryl ester are disclosed in J. Antibiot., 49(8): 815-816 (1996), and Bioorg. Med. Chem. Lett.; 6:1951-1954 (1996), respectively. Other CETP inhibitors that can be used in combination with compounds of the present invention are disclosed in WO 99/20302, EP 796846, EP818197, EP 818448, WO 99/14204, WO 99/41237, WO 95/04755, WO 96/15141, WO 96/05227, DE 19704244, DE19741051, DE 19741399, DE 19704243, DE 19709125, DE 19627430, DE 19832159, DE 19741400, JP 11049743, and JP 09059155. Preferred CETP inhibitors that can be used in combination with the compounds of the present invention include
[2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
[2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
[2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 2-hydroxy-ethyl ester;
[2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
[2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
[2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; and
[2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester,
[2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
[2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
[2S,4S] 2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester;
[2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
[2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
[2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
[2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
[2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 2-hydroxy-ethyl ester;
[2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
[2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
[2S,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; and
[2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester,
and pharmaceutically acceptable salts and prodrugs thereof and salts of the prodrugs.
Any ACAT inhibitor can serve as the second compound in the combination therapy aspect of this invention. The term ACAT inhibitor refers to compounds that inhibit the intracellular esterification of dietary cholesterol by the enzyme acyl CoA: cholesterol acyltransfer. Such inhibition may be determined readily by one of skill in the art according to standard assays, such as the method of Heider et al. described in Journal of Lipid Research., 24:1127 (1983). A variety of these compounds are described and referenced below; however, other ACAT inhibitors will be known to those skilled in the art. U.S. Pat. No. 5,510,379 discloses certain carboxysulfonates, while WO 96/26948 and WO 96/10559 both disclose urea derivatives having ACAT inhibitory activity.
Any compound having activity as a squalene synthetase inhibitor can serve as an additional compound in the combination therapy aspect of the instant invention. The term squalene synthetase inhibitor refers to compounds that inhibit the condensation of two molecules of farnesylpyrophosphate to form squalene, a reaction that is catalyzed by the enzyme squalene synthetase. Such inhibition is readily determined by those skilled in the art according to standard methodology (Methods of Enzymology, 15:393-454 (1969); and Methods of Enzymology, 110: 359-373 (1985); and references cited therein). A summary of squalene synthetase inhibitors has been complied in Curr. Op.Ther. Patents, 861-4, (1993). European patent application publication Number 0 567 026 A1 discloses certain 4,1-benzoxazepine derivatives as squalene synthetase inhibitors and their use in the treatment of hypercholesterolemia and as fungicides. European patent application publication Number 0 645 378 A1 discloses certain seven- or eight-membered heterocycles as squalene synthetase inhibitors and their use in the treatment and prevention hypercholesterolemia and fungal infections. European patent application publication Number 0 645 377 A1 discloses certain benzoxazepine derivatives as squalene synthetase inhibitors useful for the treatment of hypercholesterolemia or coronary sclerosis. European patent application publication Number 0 611 749 A1 discloses certain substituted amic acid derivatives useful for the treatment of arteriosclerosis. European patent application publication Number 0 705 607 A2 discloses certain condensed seven- or eight-membered heterocyclic compounds useful as antihypertriglyceridemic agents. PCT publication WO 96/09827 discloses certain combinations of cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors including benzoxazepine derivatives and benzothiazepine derivatives. European patent application publication Number 0 701 725 A1 discloses a process for preparing certain optically-active compounds, including benzoxazepine derivatives, having plasma cholesterol and triglyceride lowering activities. Other compounds that are marketed for hyperlipidemia, including hypercholesterolemia and which are intended to help prevent or treat atherosclerosis include bile acid sequestrants, such as Colestid(copyright), LoCholest(copyright) and Questran(copyright); and fibric acid derivatives, such as Atromid(copyright), Lopid(copyright) and Tricor(copyright). These compounds can also be used in combination with a compound of the present invention.
It is also contemplated that the compounds of the present invention be administered with a lipase inhibitor and/or a glucosidase inhibitor, which are typically used in the treatment of conditions resulting from the presence of excess triglycerides, free fatty acids, cholesterol, cholesterol esters or glucose including, inter alia, obesity, hyperlipidemia, hyperlipoproteinemia, Syndrome X, and the like.
In a combination with a compound of the present invention, any lipase inhibitor or glucosidase inhibitor may be employed. Preferred lipase inhibitors comprise gastric or pancreatic lipase inhibitors such as orlistat. Preferred glucosidase inhibitors comprise amylase inhibitors.
A lipase inhibitor is a compound that inhibits the metabolic cleavage of dietary triglycerides into free fatty acids and monoglycerides. Under normal physiological conditions, lipolysis occurs via a two-step process that involves acylation of an activated serine moiety of the lipase enzyme. This leads to the production of a fatty acid-lipase hemiacetal intermediate, which is then cleaved to release a diglyceride. Following further deacylation, the lipase-fatty acid intermediate is cleaved, resulting in free lipase, a monoglyceride and a fatty acid. The resultant free fatty acids and monoglycerides are incorporated into bile acid-phospholipid micelles, which are subsequently absorbed at the level of the brush border of the small intestine. The micelles eventually enter the peripheral circulation as chylomicrons. Accordingly, compounds, including lipase inhibitors that selectively limit or inhibit the absorption of ingested fat precursors are useful in the treatment of conditions including obesity, hyperlipidemia, hyperlipoproteinemia, Syndrome X, and the like.
Pancreatic lipase mediates the metabolic cleavage of fatty acids from triglycerides at the 1- and 3-carbon positions. The primary site of the metabolism of ingested fats is in the duodenum and proximal jejunum by pancreatic lipase, which is usually secreted in vast excess of the amounts necessary for the breakdown of fats in the upper small intestine. Because pancreatic lipase is the primary enzyme required for the absorption of dietary triglycerides, inhibitors have utility in the treatment of obesity and the other related conditions.
Gastric lipase is an immunologically distinct lipase that is responsible for approximately 10 to 40% of the digestion of dietary fats. Gastric lipase is secreted in response to mechanical stimulation, ingestion of food, the presence of a fatty meal or by sympathetic agents. Gastric lipolysis of ingested fats is of physiological importance in the provision of fatty acids needed to trigger pancreatic lipase activity in the intestine and is also of importance for fat absorption in a variety of physiological and pathological conditions associated with pancreatic insufficiency. See, for example, C. K. Abrams, et al., Gastroenterology, 92, 125 (1987).
A variety of lipase inhibitors are known to one of ordinary skill in the art. However, in the practice of the methods, pharmaceutical compositions and kits of the instant invention, generally preferred lipase inhibitors are those inhibitors that are selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valilactone, esterastin, ebelactone A, ebelactone B and RHC 80267.
The pancreatic lipase inhibitors lipstatin, 2S, 3S, 5S, 7Z, 10Z)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-7,10-hexadecanoic acid lactone, and tetrahydrolipstatin (orlistat), 2S, 3S, 5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoic acid lactone, and the variously substituted N-formylleucine derivatives and stereoisomers thereof, are disclosed in U.S. Pat. No. 4,598,089.
The pancreatic lipase inhibitor FL-386, 1-[4-(2-methylpropyl)cyclohexyl]-2-[(phenylsulfonyl)oxy]-ethanone, and the variously substituted sulfonate derivatives related thereto, are disclosed in U.S. Pat. No. 4,452,813.
The pancreatic lipase inhibitor WAY-1 21 898, 4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and the various carbamate esters and pharmaceutically acceptable salts related thereto, are disclosed in U.S. Pat. Nos. 5,512,565; 5,391,571 and 5,602,151.
The lipase inhibitor Bay-N-3176, N-3-trifluoromethylphenyl-Nxe2x80x2-3-chloro-4xe2x80x2-trifluoromethylphenylurea, and the various urea derivatives related thereto, are disclosed in U.S. Pat. No. 4,405,644.
The pancreatic lipase inhibitor valilactone, and a process for the preparation thereof by the microbial cultivation of Actinomycetes strain MG147-CF2, are disclosed in Kitahara, et al., J. Antibiotics, 40 (11), 1647-1650 (1987).
The lipase inhibitor esteracin, and certain processes for the preparation thereof by the microbial cultivation of Streptomyces strain ATCC 31336, are disclosed in U.S. Pat. Nos. 4,189,438 and 4,242,453.
The pancreatic lipase inhibitors ebelactone A and ebelactone B, and a process for the preparation thereof by the microbial cultivation of Actinomycetes strain MG7-G1, are disclosed in Umezawa, et al., J. Antibiotics, 33,1594-1596 (1980). The use of ebelactones A and B in the suppression of monoglyceride formation is disclosed in Japanese Kokai 08-143457, published Jun. 4, 1996.
The lipase inhibitor RHC 80267, cyclo-O,Oxe2x80x2-[(1,6-hexanediyl)-bis-(iminocarbonyl)]dioxime, and the various bis(iminocarbonyl)dioximes related thereto may be prepared as described in Petersen et al., Liebig""s Annalen, 562, 205-229 (1949). The ability of RHC 80267 to inhibit the activity of myocardial lipoprotein lipase is disclosed in Carroll et al., Lipids, 27, pp. 305-307 (1992) and Chuang et al., J. Mol. Cell Cardiol., 22, 1009-1016 (1990).
A glucosidase inhibitor inhibits the enzymatic hydrolysis of complex carbohydrates by glycoside hydrolases, for example amylase or maltase, into bioavailable simple sugars, for example, glucose. The rapid metabolic action of glucosidases, particularly following the intake of high levels of carbohydrates, results in a state of alimentary hyperglycemia which, in adipose or diabetic subjects, leads to enhanced secretion of insulin, increased fat synthesis and a reduction in fat degradation. Following such hyperglycemias, hypoglycemia frequently occurs, due to the augmented levels of insulin present. Additionally, it is known that both hypoglycemias and chyme remaining in the stomach promotes the production of gastric juice which initiates or favors the development of gastritis or duodenal ulcers. Accordingly, glucosidase inhibitors are known to have utility in accelerating the passage of carbohydrates through the stomach and inhibiting the absorption of glucose from the intestine. Furthermore, the conversion of carbohydrates into lipids of the fatty tissue and the subsequent incorporation of alimentary fat into fatty tissue deposits is accordingly reduced or delayed, with the concomitant benefit of reducing or preventing the deleterious abnormalities resulting therefrom.
In combination with a compound of the present invention, any glucosidase inhibitor may be employed, however, a generally preferred glucosidase inhibitor comprises an amylase inhibitor. An amylase inhibitor is a glucosidase inhibitor that inhibits the enzymatic degradation of starch or glycogen into maltose. The inhibition of such enzymatic degradation is beneficial in reducing amounts of bioavailable sugars, including glucose and maltose, and the concomitant deleterious conditions resulting therefrom.
A variety of glucosidase and amylase inhibitors are known to one of ordinary skill in the art. However, in the practice of the methods and pharmaceutical compositions of the instant invention, generally preferred glucosidase inhibitors are those inhibitors that are selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose, tendamistate, Al-3688, trestatin, pradimicin-Q and salbostatin.
The glucosidase inhibitor acarbose, O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]-xcex1-glucopyranosyl-(1xe2x86x924)-O-xcex1-D-glucopyranosyl-(1xe2x86x924)-D-glucose, the various amino sugar derivatives related thereto and a process for the preparation thereof by the microbial cultivation of Actinoplanes strains SE 50 (CBS 961.70), SB 18 (CBS 957.70), SE 82 (CBS 615.71), SE 50/13 (614.71) and SE 50/110 (674.73) are disclosed in U.S. Pat. Nos. 4,062,950 and 4,174,439 respectively.
The glucosidase inhibitor adiposine, consisting of adiposine forms 1 and 2, is disclosed in U.S. Pat. No. 4,254,256. Additionally, a process for the preparation and purification of adiposine is disclosed in Namiki et al., J. Antiobiotics, 35,1234-1236 (1982).
The glucosidase inhibitor voglibose, 3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epi-inositol, and the various N-substituted pseudo-aminosugars related thereto, are disclosed in U.S. Pat. No. 4,701,559.
The glucosidase inhibitor miglitol, (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol, and the various 3,4,5-trihydroxypiperidines related thereto, are disclosed in U.S. Pat. No. 4,639,436.
The glucosidase inhibitor emiglitate, ethyl p-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]ethoxy]-benzoate, the various derivatives related thereto and pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Pat. No. 5,192,772.
The glucosidase inhibitor MDL-25637, 2,6-dideoxy-7-O-xcex2-D-glucopyrano-syl-2,6-imino-D-glycero-L-gluco-heptitol, the various homodisaccharides related thereto and the pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Pat. No. 4,634,765.
The glucosidase inhibitor camiglibose, methyl 6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]-xcex1-D-glucopyranoside sesquihydrate, the deoxy-nojirimycin derivatives related thereto, the various pharmaceutically acceptable salts thereof and synthetic methods for the preparation thereof, are disclosed in U.S. Pat. Nos. 5,157,116 and 5,504,078.
The amylase inhibitor tendamistat, the various cyclic peptides related thereto and processes for the preparation thereof by the microbial cultivation of Streptomyces tendae strains 4158 or HAG 1226, are disclosed in U.S. Pat. No. 4,451,455.
The amylase inhibitor Al-3688, the various cyclic polypeptides related thereto, and a process for the preparation thereof by the microbial cultivation of Streptomyces aureofaciens strain FH 1656, are disclosed in U.S. Pat. No. 4,623,714.
The amylase inhibitor trestatin, consisting of a mixture of trestatin A, trestatin B and trestatin C, the various trehalose-containing aminosugars related thereto and a process for the preparation thereof by the microbial cultivation of Streptomyces dimorphogenes strains NR-320-OM7HB and NR-320-OM7HBS, are disclosed in U.S. Pat. No. 4,273,765.
The glucosidase inhibitor pradimicin-Q and a process for the preparation thereof by the microbial cultivation of Actinomadura verrucospora strains R103-3 or A10102, are disclosed in U.S. Pat. Nos. 5,091,418 and 5,217,877 respectively.
The glycosidase inhibitor salbostatin, the various pseudosaccharides related thereto, the various pharmaceutically acceptable salts thereof and a process for the preparation thereof by the microbial cultivation of Streptomyces albus strain ATCC 21838, are disclosed in U.S. Pat. No. 5,091,524.
Preferred lipase inhibitors comprise compounds selected from the group consisting of lipstatin, tetrahydrolipstatin, FL-386, WAY-121898, Bay-n-3176, valilactone, esteracin, ebelactone A, ebelactone B, RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers. The compound tetrahydrolipstatin is especially preferred.
Preferred glucosidase inhibitors comprise compounds selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose, pradimicin-Q, and salbostatin. An especially preferred glucosidase inhibitor is acarbose. Especially preferred glucosidase inhibitors further comprise amylase inhibitors that are selected from the group consisting of tendamistate, Al-3688 and trestatin.
In addition, combinations of the present invention include the use of more than one compound of the present invention, and use of compounds of the present invention with other MTP inhibitors and/or apo B secretion inhibitors.
A variety of apo B secretion/MTP inhibitors are known to one of ordinary skill in the art. Although any apo B secretion/MTP inhibitor may be used in the practice of the methods and pharmaceutical compositions of the instant invention, generally preferred apo B secretion/MTP inhibitors include those compounds that are disclosed in, for example, European Patent Application Publication Numbers EP 643057, EP 719763, EP 753517, EP 764647, EP 765878, EP 779276, EP 779279, EP 799828, EP 799829, EP 802186, EP 802188, EP 802192, and EP 802197; PCT Application Publication Numbers WO 96/13499, WO 96/33193, WO 96/40640, WO 97/26240, WO 97/43255, WO 97/43257, WO 98/16526 and WO 98/23593; and U.S. Pat. Nos. 5,595,872; 5,646,162; 5,684,014; 5,712,279; 5,739,135 and 5,789,197.
Especially preferred apo-B secretion/MTP inhibitors are those biphenyl-2-carboxylic acid-tetrahydroisoquinolin-6-yl amide derivatives disclosed in PCT Application Publication Numbers WO 96/40640 and WO 98/23593. Especially preferred apo B secretion/MTP inhibitors disclosed in PCT Application Publication Numbers WO 96/40640 and WO 98/23593, and useful in the methods and pharmaceutical compositions of the present invention, are 4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquin-6-yl]-amide and 4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide.
Another especially preferred class of apo B secretion/MTP inhibitors is disclosed in U.S. Pat. Nos. 5,595,872; 5,721,279; 5,739,135 and 5,789,197.
Especially preferred apo B secretion/MTP inhibitors disclosed in U.S. Pat. Nos. 5,595,872; 5,721,279; 5,739,135 and 5,789,197 and useful in the methods and pharmaceutical compositions of the present invention, are 9-(4-{4-[4xe2x80x2trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-butyl-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 9-{4-[4-(2-benzothiazol-2-yl-benzoylamino)-piperidin-1-yl]-butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Another class of especially preferred apo B secretion/MTP inhibitors is disclosed in PCT Application Publication Number WO 98/16526.
Especially preferred apo B secretion/MTP inhibitors disclosed in PCT Application Publication Number WO 98/16526, and useful in the methods and pharmaceutical compositions of the present invention, are [11a-R]-8-[(4-cyanophenyl)methoxy]-2-cyclopentyl-7-(prop-2-enyl)-2,3,11,11 a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione and [11 a-R]-cyclopentyl-7-(prop-2-enyl)-8-[(pyridin-2-yl)methoxy]-2,3,11,11a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione.
Another especially preferred class of apo B secretion/MTP inhibitors is disclosed in U.S. Pat. No. 5,684,014.
An especially preferred apo B secretion/MTP inhibitor disclosed in U.S. Pat. No. 5,684,014, and useful in the methods and pharmaceutical compositions of the present invention, is 2-cyclopentyl-2-[4-(2,4-dimethyl-pyrido[2,3-b]indol-9-ylmethyl)-phenyl]-N-(2-hydroxy-1-phenyl-ethyl)-acetamide.
Yet another class of especially preferred apo B secretion/MTP inhibitors is disclosed in U.S. Pat. No. 5,646,162.
An especially preferred apo B secretion/MTP inhibitor disclosed in U.S. Pat. No. 5,646,162 and useful in the methods and pharmaceutical compositions of the present invention, is 2-cyclopentyl-N-(2-hydroxy-1-phenylethyl)-2-[4-(quinolin-2-ylmethoxy)-phenyl]-acetamide.
All documents cited in this patent application are hereby incorporated by reference.
In another aspect of the present invention, the compounds of Formula I can be used in combination with another anti-obesity agent. The additional anti-obesity agents is preferably selected from the group consisting of a xcex23-adrenergic receptor agonist, a cholecystokinin-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a serotoninergic agent, a dopamine agonist, a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone receptor analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y antagonist such as NPY-1 or NPY-5, a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, a urocortin binding protein antagonist, a glucagon-like peptide-1 receptor agonist, and a ciliary neurotrophic factor.
Especially preferred anti-obesity agents comprise those compounds selected from the group consisting of sibutramine, fenfluramine, dexfenfluramine, bromocriptine, phentermine, ephedrine, leptin, phenylpropanolamine pseudoephedrine, {4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}acetic acid, {4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}benzoic acid, {4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}propionic acid, and {4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenoxy}acetic acid.